The present invention relates to heparin compositions, methods of making such compositions, and compositions prepared therefrom.
Development of materials that do not induce hostile response from the body tissues upon implantation or insertion in a human or animal body is an important target in the medical device field. In practice, many commonly used materials including plastics, ceramics, and metals have substantial biocompatibility problems.
One important property for medical devices that contact blood after implantation or insertion in a human or animal body is thrombogenicity. Thrombogenicity is the ability of the device to induce formation of blood clots. For blood to clot, it is believed that thrombin must be generated in the blood. Several potent anticoagulants are known that are able to prevent formation of thrombin. The most widely used anticoagulant used during surgical procedures is heparin. When heparin is immobilized on the surface of a medical device, the ability of the surface to induce formation of clots decreases, or in other words, the surface becomes antithrombogenic. However, the antithrombogenicity of a heparinized surface tends to decrease as the surface heparin loses its potency to retard clot formation. Many heparinized surfaces tend to have poor stability in vivo. New heparin compositions and coatings are needed to improve the antithrombogenic stability of heparinized surfaces.
A few reports of heparin compositions and methods of making and using heparin and antithrombogenic compositions have appeared in the art, some examples of which may be found in the patents and publications listed in Table 1 below.
Technical Publications
Dow Corning MDX4-4159 Fluid 50% Medical Grade Dispersion, Product Information Sheet, Copyright 2000
All patents and publications listed in Table 1 above are hereby incorporated by reference herein in their respective entireties. As those of ordinary skill in the art will appreciate readily upon reading the Summary of the Invention, Detailed Description of the Preferred Embodiments, and claims set forth below, many of the devices and methods disclosed in the patents and publications of Table 1 may be modified advantageously by using the teachings of the present invention.
The present invention has certain objects. That is, various embodiments of the present invention provide solutions to one or more problems existing in the prior art respecting heparin compositions and methods and making and using such compositions. Those problems include heparin compositions having poor solubility in organic solvents, heparin compositions having poor antithrombogenic stability, heparin compositions having poor adhesion to surfaces, heparin compositions requiring special surface treatments that may result in degradation of surface properties, heparin compositions having limited antithrombogenicity, heparin compositions having high release rates upon exposure to body fluids, heparin compositions having low release rates upon exposure to body fluids, heparin compositions with inadequate mechanical properties, heparin compositions requiring thermal treatments, heparin compositions requiring thick coating layers, and heparin compositions requiring the used of toxic chemical compounds. Various embodiments of the present invention have the object of solving at least one of the foregoing problems. While some conventional heparin compositions were capable of solving at least some of the foregoing problems, they were generally not employed because of their prohibitively high cost or difficult production processes. It is therefore another object of the present invention to provide improved heparin compositions that may be produced, used, and sold at low cost, yet still fulfill at least one of the foregoing objects.
In comparison to known heparin compositions and methods of making and using such compositions, various embodiments of the present invention may provide one or more of the following advantages. The present invention provides heparin compositions with improved properties over heparin compositions known in the art. For example, heparin compositions of the present invention are preferably soluble in organic solvents. Preferably the heparin compositions of the present invention have a solubility in isopropyl alcohol at room temperature of at least about 1% by weight, and more preferably, at least about 5% by weight. Organic solubility may be important in preventing complications including undue limitations in formulating coating fluids, difficult or inefficient coating processes, inadequate coating uniformity, and low quantity of attached or imbedded heparin. Heparin compositions of the present invention also preferably provide coating compositions with adequate adhesion to the surface of a device, preferably a medical device. Heparinized surfaces that include heparin compositions of the present invention preferably maintain antithrombogenicity after several hours under high blood flow in vivo conditions, for example, in a heart or an aorta. Preferably, heparinized surfaces that include heparin compositions of the present invention provide excellent mechanical properties and suitable electrical properties in applications including, for example, medical devices.
The present invention also provides advantageous methods for preparing heparinized surfaces. Surfaces that include heparin compositions of the present invention preferably provide sustained release of heparin upon exposure to body fluids. Methods of the present invention also allow the preparation of coating compositions that include organic soluble heparin-adducts and/or heparin complexes. Such coating compositions allow the use of coating processes that may provide economic advantages as well as product quality improvements. For example, dip-coating or spray-coating methods of the present invention preferably provide uniform coating layers. Coating uniformity may be desirable for sustained release of heparin upon exposure to body fluids.
Definitions
As used herein, xe2x80x9cadductxe2x80x9d means a covalently bonded reaction product of two named chemical species. For example, a heparin-polyoxyalkylenepolyamine adduct is a covalently bonded reaction product formed by the reaction of a heparin species with a polyoxyalkylenepolyamine.
As used herein, xe2x80x9ccomplexxe2x80x9d means an ionically bonded reaction product of a cationic species and an anionic species. For example, a quaternary ammonium heparin complex is an ionically bonded reaction product formed by the reaction of a cationic quaternary ammonium species with an anionic heparin species.
As used herein, xe2x80x9corganic solublexe2x80x9d refers to solubility in typical organic solvents including, for example, tetrahydrofuran, acetone, ethanol, isopropanol, methylene chloride, chloroform, hexane, heptane, xylenes, toluene, dioxolane, and N,N-dimethylacetamide. The organic solvent preferably does not include substantial amounts of water. The organic solvent may include at most about 10% by weight water and preferably at most about 5% by weight water. An organic soluble composition has solubility of at least about 1% by weight in isopropyl alcohol at room temperature. Preferably, an organic soluble composition has solubility of at least about 5% by weight in isopropyl alcohol at room temperature.
As used herein, xe2x80x9cwater insolublexe2x80x9d means that the composition does not have substantial solubility in water. A substantially water insoluble composition has solubility of at most about 2% by weight in water at room temperature. Preferably, a substantially water insoluble composition has solubility of at most about 0.1% by weight in water at room temperature.
As used herein, xe2x80x9cuniform coatingxe2x80x9d means that the surface is completely covered by the coating.
As used herein, xe2x80x9cmoisture curablexe2x80x9d means that curing may be initiated upon exposure to moisture (i.e., water), in either the liquid or the vapor state.
As used herein, the term xe2x80x9ccuringxe2x80x9d includes hardening, crosslinking, polymerizing, chain extending, and other related chemical reactions. Preferably a cured material has undergone sufficient hardening, crosslinking, polymerizing, or chain extending to provide a material in the solid state.
As used herein, xe2x80x9cheparinxe2x80x9d refers to a heterogeneous group of straight-chain anionic mucopolysaccharides having anticoagulant properties.